Suggestions on Improving China’s Breakthrough Therapy Designation System

Objective To analyze the characteristics of breakthrough therapy designation(BTD)and its implementation in China,and to provide reference for the optimization of BTD system.Methods A comparative research method was used to study the content and implementation effect of BTD system in China and the relevant policies and implementation of the same procedures of drug regulatory authorities in the United States,Japan and the European Union.Then,the differences in policies and implementation results among these countries were analyzed to provide suggestions for the implementation and optimization of this system in China.Results and Conclusion China’s BTD system is implemented late and a small number of drugs has been approved.At the same time,there are problems such as insufficient guidance and communication from the agency to applicants,a broad application condition,single review mode,and lack of full-time personnel.Both the agencies and the applicants have limited experience due to the short implementation time of BTD system in China.There are still some problems despite we have learned a lot from the experience of other drug regulatory agencies.Therefore,based on our national conditions,we should strengthen the guidance of evaluation agency to applicants,optimize the eligibility criteria of BTD system,introduce the rolling review,and increase the number of professional liaisons,which can accelerate the development and marketing process of drugs with obvious clinical value,and finally to address unmet medical need.

Using multivariate adaptive regression splines to develop relationship between rock quality designation and permeability

The assessment of in situ permeability of rock mass is challenging for large-scale projects such as reservoirs created by dams,where water tightness issues are of prime importance.The in situ permeability is strongly related to the frequency and distribution of discontinuities in the rock mass and quantified by rock quality designation(RQD).This paper analyzes the data of hydraulic conductivity and discontinuities sampled at different depths during the borehole investigations in the limestone and sandstone formations for the construction of hydraulic structures in Oman.Cores recovered from boreholes provide RQD data,and in situ Lugeon tests elucidate the permeability.A modern technique of multivariate adaptive regression splines(MARS)assisted in correlating permeability and RQD along with the depth.In situ permeability shows a declining trend with increasing RQD,and the depth of investigation is within 50 m.This type of relationship can be developed based on detailed initial investigations at the site where the hydraulic conductivity of discontinuous rocks is required to be delineated.The relationship can approximate the permeability by only measuring the RQD in later investigations on the same site,thus saving the time and cost of the site investigations.The applicability of the relationship developed in this study to another location requires a lithological similarity of the rock mass that can be verified through preliminary investigation at the site.

A novel approach to structural anisotropy classification for jointed rock masses using theoretical rock quality designation formulation adjusted to joint spacing

Rock quality designation(RQD)has been considered as a one-dimensional jointing degree property since it should be determined by measuring the core lengths obtained from drilling.Anisotropy index of jointing degree(AI_(jd))was formulated by Zheng et al.(2018)by considering maximum and minimum values of RQD for a jointed rock medium in three-dimensional space.In accordance with spacing terminology by ISRM(1981),defining the jointing degree for the rock masses composed of extremely closely spaced joints as well as for the rock masses including widely to extremely widely spaced joints is practically impossible because of the use of 10 cm as a threshold value in the conventional form of RQD.To overcome this limitation,theoretical RQD(TRQD_(t))introduced by Priest and Hudson(1976)can be taken into consideration only when the statistical distribution of discontinuity spacing has a negative exponential distribution.Anisotropy index of the jointing degree was improved using TRQD_(t) which was adjusted to wider joint spacing by considering Priest(1993)’s recommendation on the use of variable threshold value(t)in TRQD_(t) formulation.After applications of the improved anisotropy index of a jointing degree(AI'_(jd))to hypothetical jointed rock mass cases,the effect of persistency of joints on structural anisotropy of rock mass was introduced to the improved AI'_(jd) formulation by considering the ratings of persistency of joints as proposed by Bieniawski(1989)’s rock mass rating(RMR)classification.Two real cases were assessed in the stratified marl and the columnar basalt using the weighted anisotropy index of jointing degree(W_AI'_(jd)).A structural anisotropy classification was developed using the RQD classification proposed by Deere(1963).The proposed methodology is capable of defining the structural anisotropy of a rock mass including joint pattern from extremely closely to extremely widely spaced joints.

Effect of Professional Designation on the Level of Task Performance by Community Health Workers in Enugu State

The study aimed at assessment of level of task performance of Primary Health Care Worker （PHCWs） according to their professional designations in selected Local Government Areas （LGA） in Enugu State. Descriptive survey research was used. 291 PHCWs were randomly selected from 9 LGA using a multistage method. Questionnaire was used to collect data and the instrument was validated using test-retest method with correlation coefficient of 0.79. The findings show that Community Health Extension Workers （CHEWs） performed higher than Environmental Health Officer （EVO） and Community Health Officers （CHOs） in the area of health education concerning prevailing health problems and method of control. They scored 66.09% as against 52.8% and 60.61% for EVO and CHEW respectively. The result showed that the professional designation has no significant effect （P 〈 0.05） on the level of task performed by PHCW and their levels of task performance were low. It was recommended that public Health physicians and Nurses should be involved in the PHC in Enugu State to provide the fight supervision to the PHCW.

Correlation between the rock mass properties and maximum horizontal stress:A case study of overcoring stress measurements

Understanding the mechanical properties of the lithologies is crucial to accurately determine the horizontal stress magnitude.To investigate the correlation between the rock mass properties and maximum horizontal stress,the three-dimensional(3D)stress tensors at 89 measuring points determined using an improved overcoring technique in nine mines in China were adopted,a newly defined characteristic parameter C_(ERP)was proposed as an indicator for evaluating the structural properties of rock masses,and a fuzzy relation matrix was established using the information distribution method.The results indicate that both the vertical stress and horizontal stress exhibit a good linear growth relationship with depth.There is no remarkable correlation between the elastic modulus,Poisson's ratio and depth,and the distribution of data points is scattered and messy.Moreover,there is no obvious relationship between the rock quality designation(RQD)and depth.The maximum horizontal stress σ_(H) is a function of rock properties,showing a certain linear relationship with the C_(ERP)at the same depth.In addition,the overall change trend of σ_(H) determined by the established fuzzy identification method is to increase with the increase of C_(ERP).The fuzzy identification method also demonstrates a relatively detailed local relationship betweenσ_H and C_(ERP),and the predicted curve rises in a fluctuating way,which is in accord well with the measured stress data.

Evolutionary analysis and lineage designation of SARS-CoV-2 genomes

The pandemic due to the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the etiological agent of coronavirus disease 2019(COVID-19),has caused immense global disruption.With the rapid accumulation of SARS-CoV-2 genome sequences,however,thousands of genomic variants of SARSCoV-2 are now publicly available.To improve the tracing of the viral genomes’evolution during the development of the pandemic,we analyzed single nucleotide variants(SNVs)in 121,618 high-quality SARS-CoV-2 genomes.We divided these viral genomes into two major lineages(L and S)based on variants at sites 8782 and 28144,and further divided the L lineage into two major sublineages(L1 and L2)using SNVs at sites 3037,14408,and 23403.Subsequently,we categorized them into 130 sublineages(37 in S,35 in L1,and 58 in L2)based on marker SNVs at 201 additional genomic sites.This lineage/sublineage designation system has a hierarchical structure and reflects the relatedness among the subclades of the major lineages.We also provide a companion website(www.covid19evolution.net)that allows users to visualize sublineage information and upload their own SARS-CoV-2 genomes for sublineage classification.Finally,we discussed the possible roles of compensatory mutations and natural selection during SARS-CoV-2’s evolution.These efforts will improve our understanding of the temporal and spatial dynamics of SARS-CoV-2’s genome evolution.

Designation and Development of Central Towns: A Case Study of Shiyan

In China, central towns are an important pitch point in the urban system of a city or county. The cultivation and development of central towns is significant in completing the urban system structure and improving the overall quality of urban-rural development of a city or county. In the Municipality of Shiyan, a mountainous region in Hubei Province, the designation of central towns should not be mechanically accomplished through applying the methodology used in plain areas, but with particular focus on the location and transportation of the towns. Based on the analysis of comprehensive development potential, 14 central towns are finally designated in Shiyan in view of their favorable location and the requirement of coordinated regional development. Development strategies are also proposed for them which include the improvement of urban functions, the differentiation of development modes, the growth of industrial clusters, the development of environmental-friendly industries, the standard configuration of public service facilities, and the institutional reform and innovation which would ensure the realization of the central towns' function of agglomeration and radiation.

Emerging structures and dynamic mechanisms ofγ-secretase for Alzheimer’s disease

γ-Secretase,called“the proteasome of the membrane,”is a membrane-embedded protease complex that cleaves 150+peptide substrates with central roles in biology and medicine,including amyloid precursor protein and the Notch family of cell-surface receptors.Mutations inγ-secretase and amyloid precursor protein lead to early-onset familial Alzheimer’s disease.γ-Secretase has thus served as a critical drug target for treating familial Alzheimer’s disease and the more common late-onset Alzheimer’s disease as well.However,critical gaps remain in understanding the mechanisms of processive proteolysis of substrates,the effects of familial Alzheimer’s disease mutations,and allosteric modulation of substrate cleavage byγ-secretase.In this review,we focus on recent studies of structural dynamic mechanisms ofγ-secretase.Different mechanisms,including the“Fit-Stay-Trim,”“Sliding-Unwinding,”and“Tilting-Unwinding,”have been proposed for substrate proteolysis of amyloid precursor protein byγ-secretase based on all-atom molecular dynamics simulations.While an incorrect registry of the Notch1 substrate was identified in the cryo-electron microscopy structure of Notch1-boundγ-secretase,molecular dynamics simulations on a resolved model of Notch1-boundγ-secretase that was reconstructed using the amyloid precursor protein-boundγ-secretase as a template successfully capturedγ-secretase activation for proper cleavages of both wildtype and mutant Notch,being consistent with biochemical experimental findings.The approach could be potentially applied to decipher the processing mechanisms of various substrates byγ-secretase.In addition,controversy over the effects of familial Alzheimer’s disease mutations,particularly the issue of whether they stabilize or destabilizeγ-secretase-substrate complexes,is discussed.Finally,an outlook is provided for future studies ofγ-secretase,including pathways of substrate binding and product release,effects of modulators on familial Alzheimer’s disease mutations of theγ-secretase-substrate complexes.Comprehensive understanding of the functional mechanisms ofγ-secretase will greatly facilitate the rational design of effective drug molecules for treating familial Alzheimer’s disease and perhaps Alzheimer’s disease in general.

DESIGNATION AND APPLICATION OF A SPHERICAL LONG-WAVE SPECTRAL MODEL

A two-level,quasi-geostrophic long-wave model based on spherical coordinates was developed with the explicit part belonging to a low-order model.However,it includes not only diabatic heating,Ekman fric- tion and mountain distribution,but also parameterized forcing effects of transfer properties of transient eddies. Experiment results showed that,due to the introduction of the parameterization of transfer properties of transient eddies,remarkable improvements on characters of low-order model had been obtained.In addition to its economization in calculation and conciseness in physics as in a low-order model,the long- wave model was shown to describe the energetics and angular momentum balance of the atmosphere much more reasonably,and to present the features of zonal mean westerlies and stationary waves much more correctly than the corresponding low-order model.This kind of long-wave model was therefore regarded as suitable for theoretical research and numerical modelling of some aspects of the general circulation of the atmosphere.

Heideggefs Conception of Being-with （Mitsein） and His Simple Designation of Social and Political Reality in the Black Notebooks

Despite Heidegger insists that Being and Time cannot be read as a kind of existential philosophy, such interpretation still holds in some aspect, for in it, the main content is a special kind of phenomenology of life, even be called repeatedly as the foundation of the ontology of Being in general. The project of establishing an ontology of Being in general was ultimately never carried out. What Heidegger provides in Being and time is nothing but a phenomenology of life. It is peculiar that love and friendship as an important element of life is deliberately ignored. Such a deficiency of Heidegger, namely lacking love and friendship in fundamental ontology of Dasein, is probably the reason for his political fallacy during the II-World-War, notorious political mistake in his recent published Black Notebooks.

Optimization of polyurethane-bonded thin overlay mixture designation for airport pavement

This research explored the application potential of PUM thin-overlay technology on airport rapid maintenance.The rapid curing process of polyurethane binder determines the limited time window for mixing and construction of polyurethane-bonded mixture(PUM),which presents significant difference with hot-mix asphalt(HMA)technology.Therefore,this research investigated and optimized the mix design of PUM for airport thin-overlay technology based on its thermosetting characteristics.First,limestone and basalt were comprehensively compared as an aggregate for PUM.Then,the effects of molding and curing conditions were studied in terms of mixing time,molding method,molding parameters and curing temperature.Statistical analysis was also conducted to evaluate the effects of gradation and particle size on PUM performances based on gray relational analysis(GRA),thus determining the key particle size to control PUM performances.Finally,the internal structural details of PUM were captured by X-ray CT scan test.The results demonstrated that it only took 12 hours to reach 75%of maximum strength at a curing temperature of 50°C,indicating an efficient curing process and in turn allowing short traffic delay.The internal structural details of PUM presented distribution of tiny pores with few connective voids,guaranteeing waterproof property and high strength.

A Review:From Aquatic Lives Locomotion to Bio-inspired Robot Mechanical Designations

With the development of camera technology,high-speed cameras have greatly contributed to capturing the movement and posture of animals,which has dramatically promoted experimental biology research.At the same time,with the concept of bionics gradually gaining popularity among researchers,the design of robots is absorbing more and more biological features,where the interest in the bio-inspired robot is hewed out.Compared with the traditional robot,the bio-inspired robot imitates the motion pattern to achieve similar propulsion features,which may be more effective and reasonable.In this paper,the motion patterns of aquatic animals are divided into four categories according to their propulsion mechanisms:drag-based,lift-based,jet-based,and interface-based.And bio-inspired robots imitating aquatic prototypes are introduced and reviewed.Finally,the prospect of aquatic bio-inspired robots is discussed.

水田动力底盘逆向建模与质心验证——基于Geomagic Design X

针对目前农业机械仿真和优化模型精度不高的问题,提出了一种构建精确模型的逆向建模方法。应用光学扫描仪采集点云数据,基于Geomagic Design X处理点云数据并重构零部件模型,在SolidWorks中完成水田动力底盘的装配。以VP6D-CQ型水田动力底盘为例,将测得的实际质心位置与所建的模型质心位置进行比较,并对提出的逆向建模方法进行了试验验证以及误差分析。结果表明:总质量、x坐标、y坐标、z坐标的误差值分别为4.55%、3.62%、2.23%、4.81%,误差值均在5%内。此方法可构建准确的三维模型,为后续仿真优化数据精确性奠定了基础,与传统的研发相比较,可缩短农业机械研发周期、降低设计成本。

车载信息交互系统复杂性设计管理发展研究

目的梳理车载信息交互系统及其复杂性管理的发展脉络,并提出多元设计策略以指导车载信息交互系统设计。方法首先利用Vosviewer进行文献检索,梳理出目前车载信息交互领域的研究热点;然后通过文献回顾的方式总结传统车载信息交互系统的复杂性演变;最后利用Design X的设计策略,从用户、系统、信息等角度,分析数智时代下的车载信息交互系统存在的任务复杂性及交互复杂性。结论基于Design X的设计策略,从用户群体分析、车载信息优化、智慧交通系统搭建等角度,提出有关管理车载信息交互系统复杂性的多元设计策略,为后续车载信息交互设计提供参考。

App Designer辅助教学方法探索与实践——以软件无线电课程为例

软件无线电作为通信学科的必修课程,具有承上启下的重要作用。因课程原理抽象、理论公式复杂,学员在学习过程存在理解掌握难、实践应用难等问题。通过对当前软件无线电教学过程中存在的不足与困难进行分析,提出利用MATLAB App Designer辅助课程教学,从教学准备、课堂互动、自主实验、反馈提升四个方面开展课程教学改革。实践表明,该方法对于提升学员的工程思维、系统思维具有显著效果,同时可以增强学员理论联系实际的能力。

基于MATLAB的射频微波电路阻抗匹配教学软件设计

阻抗匹配是射频微波电路设计的重要内容,然而阻抗匹配方案众多且计算繁杂,原有教学大多以中心频率匹配的数学公式推导为主,学生难以理解不同匹配方案在较宽频带内的整体性能表现。为此,基于MATLAB App Designer开发了一款阻抗匹配设计和分析软件,可实现包含集总参数电感电容和分布参数微带线在内的多种宽带、窄带匹配方案,通过输入技术指标要求便可直接得到对应的电路结构、元件值以及S参数曲线。该软件操作简单、实时性强,可快速比较多种匹配方案的性能,加强学生对阻抗匹配的深层次理解,极大地辅助了教学和科研。

用于化学品数据查询和TNT当量计算软件的研究与实现

本文介绍了一款基于Matlab App designer的化学品查询、WTNT、NTNT计算和数据保存的软件——化学品数据查询和TNT当量计算软件。该软件能够通过CAS检索服务号查询化学品相关信息,包括闪点、爆炸极限、自燃点、火灾危险性分类,并计算WTNT和NTNT,同时还支持数据保存功能。阐述了系统的功能模块和开发过程,介绍了系统的操作方法和使用效果,为化学品数据查询和TNT当量计算提供了一种简便、快捷的方法。

电驱动矿用自卸车轮毂驱动系统动态疲劳可靠性分析

针对在设计阶段无法准确评估实际载荷下轮毂驱动系统可靠性的问题,提出了一种适用于设计阶段的轮毂驱动系统可靠性评估方法。以额定设计静载荷代替实际随机载荷,计算了轮毂驱动系统各个齿轮副动态疲劳可靠性。并通过Romax Design软件模拟试验了实际载荷下的轮毂驱动系统各个齿轮副的疲劳损伤与可靠性,验证了此方法的可行性,为轮毂驱动系统的可靠性设计提供了理论依据和实际试验指导。

基于MVVM模式SpringBoot框架的高校信息化项目管理系统

传统的Java EE应用以Spring MVC、Mybatis、FreeMarker为核心,具有架构分层不清晰、前后端代码耦合性高、不易扩展等缺点。为提高轻量级Java EE应用的开发效率,提出一种基于Ant Design、React、SpringBoot、Apache Cayenne框架的Java EE应用架构。其基于MVVM模式,以SpringBoot为核心向上集成Ant Design和React为前端,向下集成Apache Cayenne为后端,集成后的架构通过Ant Design和React实现表示层,通过SpringBoot实现控制层和业务逻辑层,通过Apache Cayenne实现数据持久层。基于此开发的高校信息化项目管理系统,架构层次清晰,前后端代码彻底分离,可供高校信息化项目管理部门使用和推广。

Alloy design for laser powder bed fusion additive manufacturing:a critical review

Metal additive manufacturing(AM)has been extensively studied in recent decades.Despite the significant progress achieved in manufacturing complex shapes and structures,challenges such as severe cracking when using existing alloys for laser powder bed fusion(L-PBF)AM have persisted.These challenges arise because commercial alloys are primarily designed for conventional casting or forging processes,overlooking the fast cooling rates,steep temperature gradients and multiple thermal cycles of L-PBF.To address this,there is an urgent need to develop novel alloys specifically tailored for L-PBF technologies.This review provides a comprehensive summary of the strategies employed in alloy design for L-PBF.It aims to guide future research on designing novel alloys dedicated to L-PBF instead of adapting existing alloys.The review begins by discussing the features of the L-PBF processes,focusing on rapid solidification and intrinsic heat treatment.Next,the printability of the four main existing alloys(Fe-,Ni-,Al-and Ti-based alloys)is critically assessed,with a comparison of their conventional weldability.It was found that the weldability criteria are not always applicable in estimating printability.Furthermore,the review presents recent advances in alloy development and associated strategies,categorizing them into crack mitigation-oriented,microstructure manipulation-oriented and machine learning-assisted approaches.Lastly,an outlook and suggestions are given to highlight the issues that need to be addressed in future work.